1. Field of the Invention
The chemical processes of the present invention produce certain members of the class of antibacterial agents called cephalosporins.
2. Description of the Prior Art
Cefoperazone (T-1551), 7-[D(-)-.alpha.-(4-ethyl-2,3-dioxo-1-piperazinylcarboxamido)-.alpha.-(4-hy droxyphenyl)acetamido]-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4 -carboxylic acid, is a semisynthetic cephalosporin first reported by Toyama Chem. Ind. (Japan) and disclosed, for example, in general terms in U.S. Pat. No. 4,087,424 with a precursor acid named at column 40, line 57 of that patent. It has a broader spectrum of antibacterial activity than other cephalosporins including cefamandole and cefazolin and is significantly active against Ps. aeruginosa, Ser. marcescens and Ent. cloacae (ref. 15).
Cefoperazone is under clinical investigation (phase III) in Japan being developed by Toyama and in the U.S. by Pfizer. Because of its potentiality to become a promising product, various procedures have been reported for the preparation of cefoperazone (ref. 1-ref. 13). They are classified into four methods, A to D, as shown in Table 1.
TABLE 1 __________________________________________________________________________ Published methods of cefoperazone (CPZ) __________________________________________________________________________ Method A: 7-N-Acylation of the 3-thiolated 7-ACA or its equivalents (ref. 1-ref. 10) ##STR3## (a) RNH.sub.2 ; ref. 1-ref. 5 (b) RNCO; ref. 6 ##STR4##
Method B: .alpha.-N-Acylation of the 3-thiolated 7-p-hydroxy- phenylglycyl cephalosporin (ref. 11) Method C: 3'-Thiolation of the 3'-acetoxy derivative (ref. 12) ##STR5## Method D: Cyclization to the dioxopiperazine ring (ref. 13) ##STR6## __________________________________________________________________________ References- (1) I. Saikawa et al., Yakugaku Zasshi, 99, 929 (1979). (2) Japan Kokai 5170788 (6/18/76, Toyama). (3) Japan Kokai 52106883 (9/7/77, Toyama). (4) Japan Kokai 5448784 (4/17/79, Toyama). (5) Japan Kokai 5452090 (4/24/79, Toyama). (6) Japan Kokai 5318595 (2/20/78, Toyama). (7) Japan Kokai 5239694 (3/28/77, Toyama). (8) Japan Kokai 52151187 (12/15/77, Toyama). (9) Japan Kokai 5344584 (4/2/78, Toyama). (10) Japan Kokai 5315394 (2/13/78, Toyama). (11) Japan Kokai 5287189 (7/20/77, Toyama). (12) Japan Kokai 51113890 (10/7/76, Toyama). (13) Japan Kokai 5236684 (3/22/77, Toyama). (14) I. Saikawa et al., Yakugaku Zasshi, 97, 980 (1977). (15) N. Matsubara et al., Antimicrob. Agents Chemother., 16, 731 (1979).
The synthesis of peptides by activation of a carboxyl group using its thiolester has been reviewed in The Peptides, Volume I, Methods of Peptide Synthesis, Academic Press, N.Y. (1965) on pages 105-108 and in chemistry of the Amino Acids, Volume 2, John Wiley and Sons, Inc., N.Y. (1961) on pages 1027-1048.
In the field of cephalosporins it is common to make general reference to acylations of primary amino groups using an acid in the form of "an active ester or thiolester (e.g., with p-nitrophenol, 2,4-dinitrophenol, thiophenol, thioacetic acid)" as in column 8 of U.S. Pat. No. 4,198,504. That patent also provides examples of other patents disclosing the production of .alpha.-aminoarylacetamidocephalosporanic acids and refers to U.S. Pat. No. 4,061,748 for a disclosure of acylation of such compounds with an activated derivative of the acid having the formula ##STR7##
Derwent's Farmdoc abstract 78288B reports the reaction of 7-aminocephalosporanic acid with the thiolester having the formula ##STR8## wherein R is hydrogen or methyl to produce cefazolin (where R is methyl) and ceftezole (where R is hydrogen) having the formula ##STR9## (and see also Farmdoc 75634 and European Patent Application 4570).